GB1293590A - New penicillanic acid derivatives - Google Patents

Abstract

1293590 Amidino-penicillanic acids LOVENS KEMISKE FABRIK PRODUKTIONSAK TIESELSKAB 10 Nov 1970 [11 Nov 1969 8 July 1970] 55209/69 and 33211/70 Headings C2A and C2C Novel amidino-penicillanic acid derivatives of Formula I: and salts thereof, wherein R<SP>1</SP> and R<SP>2</SP> each represent an aliphatic hydrocarbon radical, a mono- or bi-cyclic aryl radical, a cycloalkyl radical, a cycloalkyl-alkyl radical, a heterocyclic radical or a heterocyclically substituted alkyl radical, which radicals may be substituted, e.g. by one or more halogen atoms or alkyl, hydroxy, alkoxy, alkylthio, acyl, carboxy, carbalkoxy, carbamyl, carbamido, cyano, sulphonyl, amino or substituted amino radicals, or R<SP>1</SP> and R<SP>2</SP> together with the common nitrogen atom form a ring system, and R<SP>3</SP> is hydroxyl or substituted hydroxyl, are prepared by either (a) reacting a reactive derivative of an amide or thioamide of formula where R<SP>5</SP> is oxygen or sulphur, with a 6-aminopenicillanic acid ester, or (b) reacting an amine of formula R<SP>1</SP>R<SP>2</SP>NH with a reactive derivative of a 6-formamidopenicillanic acid ester, and, if required, subsequently hydrolysing the ester group. Reactive derivatives of the amides may be the amide halide, the amide dialkyl sulphate complex or the amide acetal; the thioamides are used as a thioamide alkyl halide complex. The 6-formamidopenicillanic acid ester reactive derivative is preferably obtained by reacting 6-APA with a 1,1-dihalodimethyl ether. Chloral is reacted with each of the following: hexamethylene-imine, formamide, and #-N- butylaminopropionitrile to give respectively: N - formylhexamethyleneimine, N - ethyl - N - #- ethoxyethylformamide and N - butyl - # - formamidopropionitrile. The said compounds are each treated with oxalyl chloride to give the corresponding chloroformiminium chlorides. Chloro - (methyl - carbomethoxymethyl) - formiminium chloride is obtained by treating methyl N-formyl-N-methylglycinate with phosgene. A methyl iodide complex of N-thioformylhexamethyleneimine is prepared by reacting these component compounds. N - Formylhexamethyleneimine - dimethyl sulphate complex is analogously prepared, and is reacted with sodium methoxide to form 1-hexamethyleneiminecarboxaldehyde-dimethyl acetal. Pharmaceutical compositions having antibiotic activity against gram-negative bacteria comprise a penicillanic-acid of Formula I as defined above or a pharmaceutically acceptable salt thereof or an ester thereof which is hydrolysable in the human body, together with a pharmaceutical carrier.